The circadian timing system is closely and reciprocally tied to reward systems mediating alcoholism. Using alcohol to mitigate work-related sleep/wake disturbances creates a vicious cycle of alcohol dependence and circadian disruption. This proposal will focus on delineating the compounding effects of nature (clock gene and neurotransmitter tonus) and nurture (environment) that disrupt circadian entrainment and promote alcohol dependence and alcoholism. A Per2-deficent mouse strain, a rotating schedule of simulated shift work, and constant dark/photic conditions will be utilized for: (1) The first assessment of the interactions of environmental disruptions and Per2 clock gene deletions on potentiated alcohol preference and relapse risk and altered circadian alcohol intake;(2) The first observation of the rescuing effects of the glutamate antagonist and alcohol relapse drug, acamprosate, on potentiated alcohol preference and relapse risk associated with environmental disruptions and/ or Per2 clock gene deletions;and (3) The first exploration of areas of the circadian timing and alcohol reward systems mediating acamprosate reduction of alcohol preference and relapse risk. The central hypothesis is that environmental disturbances, Per2 clock gene deletions, and related hyperglutamatergic states greatly potentiate alcohol preference and relapse risk, and that such potentiation can be rescued by systemic and intra-cranial acamprosate treatment. The proposed research addresses limitations from previous shift work and acamprosate studies, and optimally, will improve the quality of pharmacological and behavioral therapies available for the treatment of alcoholism. PUBLIC HEALTH RELEVANCE: This proposal will illustrate environmental (rotating shift work) and genetic (deletions) contributions to alcohol dependence and relapse risk. It will also localize areas of the central nervous system mediating alcohol dependence and relapse risk. This research shows the need for a combination of pharmacological and behavioral therapies for the treatment of alcoholism and prevention of relapse.